Therapeutic heterocyclic compounds

ABSTRACT

Compounds of formula (I) ##STR1## wherein R and R 1  are hydrogen, C 1-4  alkyl or are linked to form a ring, 
     A is a cycloalkyl or alkyl-cycloalkyl group, 
     n is an integer from 0 to 3, 
     W is an optionally substituted 5- or 6-membered heterocyclic ring; or W is an optionally substituted aryl, heteroaryl, aryloxy or thiophenoxy group; or 
     W is a group --SO 2  NR 6  R 7  --NHC(O)R 6  R 7  or --C(O)NHR 6  R 7  ; 
     are useful in treating clinical conditions for which a &#34;5-HT 1  -like&#34; receptor agonist is indicated.

This is a division of application Ser. No. 09/008,833, filed Jan. 20,1998, which is a division of Ser. No. 08/682,615 filed Oct. 7, 1996, nowU.S. Pat. No. 5,744,466, which is a 371 of PCT/GB95/00142 filed Jan. 25,1995.

The present invention is concerned with new chemical compounds, theirpreparation, pharmaceutical formulations containing them and their usein medicine, particularly the prophylaxis and treatment of migraine.

Receptors which mediate the actions of 5-hydroxytryptamine (5-HT) havebeen identified in mammals in both the periphery and the brain.Currently, as many as seven 5-HT receptor classes are proposed (Hoyer elal., Pharmacol. Rev., 46, 157-203, 1994), although only the classesnominated 5-HT₁, 5-HT₂, 5-HT₃, and 5-HT₄ have established physiologicalroles. European Patent Specification 0313397 describes a class of 5-HTagonists which act selectively at a particular subtype of 5-HT₁ receptorand are effective therapeutic agents for the treatment of clinicalconditions in which a selective agonist for this type of receptor isindicated. For example, the receptor in question mediates selectivecranial arterial vasoconstriction and inhibition of plasma proteinextravasation into the dura mater evoked by activation of the Vth(trigeminal) nerve. The compounds described in the Europeanspecification are therefore beneficial in the treatment or prophylaxisof conditions wherein these actions are indicated, for example,migraine, a condition associated with and/or neurogenically-evokedinflammation dilation of the cranial vasculature. However, it is withinthe scope of the earlier application that the target tissue may be anytissue wherein action is mediated by 5-HT₁ receptors of the typereferred to above.

EP-A-0486666 discloses a class of compounds having exceptional activityat the 5-HT₁ receptor mentioned above and excellent absorption followingoral dosing. These properties render the compounds particularly usefulfor certain medical applications, notably the prophylaxis and treatmentof migraine, cluster headache and headache associated with vasculardisorders, hereinafter referred to collectively as "migraine".

There has now been discovered a class of compounds which not onlydemonstrate improved metabolic stability and the necessary 5HT₁ receptoragonism, but also display a potentially selective inhibition ofneurogenic inflammation and the nerve pathways responsible for thetransmission of head pain. The compounds also display partial agonism atthe 5HT₁ receptor and thus may have reduced side effects compared topreviously known 5HT₁ receptor agonists.

Thus, according to a first aspect of the present invention there isprovided a compound of formula (I): ##STR2## wherein R and R¹ are eachindependently hydrogen or C₁₋₄ alkyl or R and R¹ are linked to form anazetidine ring;

A is C₃₋₆ cycloalkyl or C₁₋₃ alkyl-C₃₋₆ cycloalkyl;

n is an integer of from 0 to 3;

W is a five or six membered ring containing from 1 to 3 hetero atomsindependently selected from nitrogen, oxygen, and sulphur, said ringbeing optionally substituted by one or more substituents independentlyselected from C₁₋₄ alkyl C₃₋₈ cycloalkyl, carbonyl or sulphonyl andoptionally said ring is fused to a phenyl ring; or W is an aryl,heteroaryl, aryloxy or thiophenoxy group containing from 1 to 8 carbonatoms said group being optionally substituted by one or moresubstituents independently selected from C₁₋₄ alkyl, phenyl, amino ormono- or di- C₁₋₄ alkylamino, and said heteroaryl group containing from1 to 4 heteroatoms independently selected from nitrogen, oxygen andsulphur; or W is a group--SO₂ NR⁶ R⁷ --NHC(O)R⁶ R⁷ or --C(O)NHR⁶ R⁷wherein R⁶ and R⁷ are independently selected from hydrogen, C₁₋₄ alkyloptionally substituted by an aryl group or C₁₋₄ alkoxy;

and salts, solvates and physiologically functional derivatives thereof;

with the proviso that said compound is not3-[cis-1-N,N-dimethylamino)cyclobutan-3-yl]-5-(1,2,4-triazol-1-ylmethyl)-H-indoleor

3-[trans-1-N,N-dimethylamino)cyclobutan-3-yl]-5-(1,2,4-triazol-1-ylmethyl)-H-indole

Compounds of formula (I) wherein A is C₃₋₆ cycloalkyl are particularlysuitable.

Preferably, R and R¹ are each independently hydrogen or C₁₋₄ alkyl.

In suitable compounds of Formula (I) W is a five or six-membered ringcontaining from 1 to 3 hetro atoms independently selected from nitrogen,oxygen and sulphur, said ring being optionally substituted by one ormore substituents independently selected from C₁₋₄ alkyl, C₃₋₈cycloalkyl, carbonyl or sulphonyl and optionally said ring is fused to aphenyl ring; or W is a group SO₂ NR⁶ R⁷ wherein R⁶ and R⁷ areindependently hydrogen or C₁₋₄ alkyl.

Particularly suitable compounds of formula (I) include those wherein:

R and R¹ are each independently hydrogen or C₁₋₄ alkyl;

A is C₃₋₆ cycloalkyl;

n is an integer of from 0 to 3;

W is a five or six-membered ring containing from 1 to 3 hetero atomsindependently selected from nitrogen, oxygen and sulphur, said ringbeing optionally substituted by one or more substituents independentlyselected from C₁₋₄ alkyl, C₃₋₈ cycloalkyl, carbonyl or sulphonyl andoptionally said ring is fused to a phenyl ring;

or W is a group SO₂ NR⁶ R⁷ wherein R⁶ and R⁷ are independently hydrogenor C₁₋₄ alkyl; and salts solvates and physiologically functionalderivatives thereof,

with the proviso that said compounds are not3-[cis-1-(N,N-dimethylamino)cyclobutan-3-yl]-5-(1,2,4-triazol-1-ylmethyl)-H-indoleor

3-[trans-1-(N,N-dimethylamino)cyclobutan-3-yl]-5-(1,2,4-triazol-1-ylmethyl)-H-indole

Compounds of formula (I) wherein A is C₃ or C₄ cycloalkyl areparticularly suitable, with compounds wherein A is C₄ cycloalkyl beingpreferred.

Accordingly, in a second aspect the present invention provides acompound of formula (Ia): ##STR3## wherein Ra and Ra¹ are eachindependently hydrogen or C₁₋₄ alkyl;

n is an integer of from 0 to 3;

Wa is a five or six membered ring containing from 1 to 3 hetero atomsindependently selected from nitrogen, oxygen and sulphur, said ringbeing optionally substituted by one or more substituents independentlyselected from C₁₋₄ alkyl, C₃₋₈ cycloalkyl, carbonyl or sulphonyl andoptionally said ring is fused to a phenyl ring, or Wa is a group SO₂ NR⁸R⁹ wherein R⁸ and

R⁹ are independently hydrogen or C₁₋₄ alkyl;

and salts, solvates and physiologically functional derivatives thereof;

with the proviso that said compound is not3-[cis-1-(N,N-dimethylamino)cyclobutan-3-yl]-5-(1,2,4-triazol-1-ylmethyl)-H-indoleor

3-[trans-1-(N,N-dimethylamino)cyclobutan-3-yl]-5-(1,2,4-triazol-1-ylmethyl)-H-indole

W in formula (I) or Wa in formula (Ia) includes the following groups(i), (ii), (iii), (iv), (v), (vi), (vii), (viii) or (ix): ##STR4##wherein R², R³, and R⁴, are hydrogen or C₁₋₄ alkyl; R⁵ is hydrogen orNR¹⁰ R¹¹, wherein R¹⁰ and R¹¹ are hydrogen or C₁₋₄ alkyl;

E is --C═ or N;

F is N when E is --C═ or F is ═C-- when E is N;

X is --O--, --S--, --NH-- or --CH₂ --;

Y is oxygen or sulphur,

Z is --NH-- or --S--; and

B is C₃₋₈ cycloalkyl and the chiral centre * in formula (i) or (ii) isin its (S) or (R) form or is a mixture thereof in any proportions;

Suitably X is --O--. Further suitable groups W or Wa are those in whichY is oxygen. Preferred groups W and Wa are those of formulae (i) and(ii). A particularly preferred group W or Wa is that of formula (i)wherein X is --O--, Y is oxygen and R² is hydrogen.

Examples of preferred compounds of the invention include:

4-[3-(trans-3-aminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)oxazolidin-2-one.

4-[3-(trans-3-aminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)oxazolidin-2-oneacetate.

4-[3-(cis-3-aminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)oxazolidin-2-oneacetate.

4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)oxazolidin-2-one.

5-(5,5-dimethyl)-3-{2-[3-trans-3-dimethylaminocyclobutyl)-1H-indol-5-yl]ethyl}imidazolidin-2,4-dione

3-{2-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-yl]ethyl}imidazolidin-2,4-dione.

3-{2-[3-(trans-3-aminocyclobutyl)-1H-indol-5-yl]ethyl}-5,5-dimethylimidazolid2,4-dione.

2-{2-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-yl]ethyl}phthalamide.

3-{2-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-yl]ethyl}-3-azaspiro[5,5]undecane-2,4-dione.

N-methyl-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-yl]methanesulphonamide.

4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylnethyl]-(4R)oxazolidin-2-one.

4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-3-methyl(4S)-oxazolidin-2-one.

5,5-dimethyl-3-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]imidazolidin-2,4-dione.

3-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]imidazolidin-2,4-dione.

5-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]oxazolidin-2-one.

4-[3-(trans-3-dimethylaminocyclobut-1-ylmethyl)-1H-indol-5-ylmethyl]-(4S)oxazolidin-2-one.

4-[3-(trans-3-methylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)oxazolidin-2-one.

4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-3-methyl(4R)oxazolidin-2-one.

3-(trans)-3-dimethylaminocyclobutyl)-1H-indol-5-yl acetamide.

4-[3-(cis-3-dimethylaminocyclobutyl-1H-indol-5ylmethyl]-(4S)oxazolidin-2-one.

5-phenoxy-3-(trans-3-aminocyclobutyl)-1H-indole.

5-phenoxy-3-(trans-3-dimethylaminocyclobutyl)-1H-indole.

N-benzyl-3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-yl acetamide.

5-N-benzylcarboxamido-3-(trans-3-dimethylaminocyclobutyl)-1H-indole.

3-methyl-5-[3-(trans-3-dimethylaminocyclobutyl)indol-5-yl]-1,2,4-oxadiazole.

3-methyl-5-[3-(trans-3-dimethylaminocyclobutyl)indol-5-ylmethyl]-1,2,4-oxadiazole.

3-methyl-5-[3-trans-3-dimethylaminocyclobutyl)indol-5-ylmethyl]-1,2,4-triazole.

(S)-2-(5-(2-Oxo-4-oxazolidinylmethyl)-1H-indol-3-yl)cyclopropylarnine.

5-carboxamido-3-(trans-3-dimethylaminocyclobutyl)-1H-indole.

Physiologically acceptable salts are particularly suitable for medicalapplications because of their greater aqueous solubility relative to theparent, ie basic, compounds. Such salts must clearly have aphysiologically acceptable anion. Suitable physiologically acceptablesalts of the compounds of the present invention include those derivedfrom acetic, hydrochloric, hydrobromic, phosphoric, malic, maleic,fumaric, citric, sulphuric, lactic, or tartaric acid. The succinate andchloride salts are particularly preferred for medical purposes. Saltshaving a non-physiologically acceptable anion are within the scope ofthe invention as useful intermediates for the preparation ofphysiologically acceptable salts and/or for use in non-therapeutic, forexample, in vitro situations.

According to a third aspect of the present invention, there is provideda compound of formula (I) or (Ia) or a physiologically acceptable salt,solvate, or physiologically functional derivative thereof for use as atherapeutic agent, specifically as a "5-HT₁ -like" receptor agonist, forexample, as a carotid vasoconstrictor or as an inhibitor of neurogenicinflammation in the prophylaxis and treatment of migraine. As indicated,however, target organs for the present compounds other than the carotidvasculature are within the scope of the present invention.

The amount of a compound of formula (I) or (Ia), or a salt or solvatethereof, which is required to achieve the desired biological effect willdepend on a number of factors such as the specific compound, the use forwhich it is intended, the means of administration, and the recipient. Atypical daily dose for the treatment of migraine may be expected to liein the range 0.01 to 5 mg per kilogram body weight. Unit doses maycontain from 1 to 100 mg of a compound of formula (I) or (Ia), forexample, ampoules for injection may contain from 1 to 10 mg and orallyadministrable unit dose formulations such as tablets or capsules maycontain from 1 to 100 mg. Such unit doses may be administered one ormore times a day, separately or in multiples thereof An intravenous dosemay be expected to lie in the range 0.01 to 0.15 mg/kg and wouldtypically be administered as an infusion of from 0.0003 to 0.15 mg perkilogram per minute. Infusion solutions suitable for this purpose maycontain from 0.01 to 10 mg/ml.

When the active compound is a salt or solvate of a compound of formula(I) the dose is based on the cation (for salts) or the unsolvatedcompound.

Hereinafter references to "compound(s) of formula (I) or (Ia)" will beunderstood to include physiologically acceptable salts and solvatesthereof

According to a fourth aspect of the present invention, therefore, thereare provided pharmaceutical compositions comprising, as activeingredient, at least one compound of formula (I) or (Ia) and/or apharmacologically acceptable salt or solvate thereof together with atleast one pharmaceutical carrier or excipient. These pharmaceuticalcompositions may be used in the prophylaxis or treatment of clinicalconditions for which a "5-HT₁ -like" receptor agonist is indicated, forexample, migraine. The carrier must be pharmaceutically acceptable tothe recipient and must be compatible with, i.e. not have a deleteriouseffect upon, the other ingredients in the composition. The carrier maybe a solid or liquid and is preferably formulated with at least onecompound of formula (I) or (Ia) as a unit dose formulation, for example,a tablet which may contain from 0.05 to 95% by weight of the activeingredient. If desired, other physiologically active ingredients mayalso be incorporated in the pharmaceutical compositions of theinvention.

Possible formulations include those suitable for oral, buccal,parenteral (for example, subcutaneous, intramuscular, or intravenous),rectal, topical and intranasal administration. The most suitable meansof administration for a particular patient will depend on the nature andseverity of the condition being treated and on the nature of the activecompound, but, where possible, oral administration is preferred.

Formulations suitable for oral administration may be provided asdiscrete units, such as tablets, capsules, cachets, or lozenges, eachcontaining a predetermined amount of the active compound; as powders orgranules; as solutions or suspensions in aqueous or non-aqueous liquids;or as oil-in-water or water-in-oil emulsions.

Formulations suitable for sublingual or buccal administration includelozenges comprising the active compound and, typically, a flavouredbase, such as sugar and acacia or tragacanth, and pastilles comprisingthe active compound in an inert base, such as gelatin and glycerin orsucrose and acacia.

Formulations suitable for parenteral administration typically comprisesterile aqueous solutions containing a predetermined concentration ofthe active compound; the solution is preferably isotonic with the bloodof the intended recipient. Although such solutions are preferablyadministered intravenously, they may also be administered bysubcutaneous or intramuscular injection.

Formulations suitable for rectal administration are preferably providedas unit-dose suppositories comprising the active ingredient and one ormore solid carriers forming the suppository base, for example, cocoabutter.

Formulations suitable for topical or intranasal application includeointments, creams, lotions, pastes, gels, sprays, aerosols and oils.Suitable carriers for such formulations include petroleum jelly,lanolin, polyethylene glycols, alcohols, and combinations thereof. Theactive ingredient is typically present in such formulations at aconcentration of from 0.1 to 15% w/w.

The formulations of the invention may be prepared by any suitablemethod, typically by uniformly and intimately admixing the activecompound(s) with liquids or finely divided solid carriers, or both, inthe required proportions and then, if necessary, shaping the resultingmixture into the desired shape.

For example, a tablet may be prepared by compressing an intimate mixturecomprising a powder or granules of the active ingredient and one or moreoptional ingredients, such as a binder, lubricant, inert diluent, orsurface active dispersing agent, or by moulding an intimate mixture ofpowdered active ingredient and inert liquid diluent.

Aqueous solutions for parenteral administration are typically preparedby dissolving the active compound in sufficient water to give thedesired concentration and then rendering the resulting solution sterileand isotonic.

Thus, according to a fifth aspect of the present invention, there isprovided the use of a compound of formula (I) or (Ia) in the preparationof a medicament for the prophylaxis or treatment of a clinical conditionfor which a "5-HT₁ -like" receptor agonist is indicated, for example,migraine.

According to a sixth aspect, there is provided a method for theprophylaxis or treatment of a clinical condition in a mammal, forexample, a human, for which a "5-HT₁ -like" receptor agonist isindicated, for example, migraine, which comprises the administration tosaid mammal of a therapeutically effective amount of a compound offormula (I) or (Ia) or of a physiologically acceptable salt, solvate, orphysiologically functional derivative thereof.

In a further aspect the invention provides a process for the preparationof compound of formula (I) by reacting a compound of formula (II)##STR5## wherein n and W are as hereinbefore defined, with a compound offormula (III) ##STR6## wherein A is as hereinbefore defined and Z is abenzyloxycarbonyl group, to give a compound of formula I wherein R andR¹ are both hydrogen. The reaction is typically carried out by heatingthe compounds at a non-extreme temperature suitably in the range 50 to100° C. and preferably at about 80° C. in the presence of an aqueousmineral acid e.g. sulphuric acid and then removing the benzyloxycarbonylgroup by refluxing in a polar solvent system, for example formic acid inmethanol, in the presence of a catalyst such as palladium on carbon.

Compounds of formula (Ia) can be prepared by reacting a compound offormula (II) wherein W is Wa with a compound of formula (III) wherein Ais cyclobutyl.

Standard N-alkylation methods may be used to convert compounds offormula (I) or (Ia) wherein R and R¹ are hydrogen to correspondingcompounds wherein R and/or R¹ are C₁₋₄ alkyl.

Compounds of formula (I) or (Ia) wherein R=R¹ =C₁₋₄ alkyl may beprepared from the corresponding compound wherein R=R¹ =H by methods ofN,N-dialkylation well known to those skilled in the art, for example, bytreatment with the appropriate aldehyde in the presence of a reducingsystem, for example, sodium cyanoborohydride acetic acid, in a polarsolvent, such as methanol.

Compounds of formula (I) or (Ia) wherein R or R¹ =C₁₋₄ alkyl may beprepared from the corresponding compound wherein R=R¹ =H byN-benzylation using benzaldehyde and a suitable reducing agent, forexample sodium borohydride, in a polar solvent such as ethanol, followedby N-alkylation using a suitable agent, such as the appropriatedialkylsulphate, typically in the presence of a base, for exampleanhydrous potassium carbonate, in a polar aprotic solvent, such as DMF,and finally N-debenzylation, typically by catalytic hydrogenation using,for example Pd/C in a polar solvent such as ethanol.

Compounds of formula (III) may be prepared from the appropriate3-methylenecycloalkane-1-carboxylic acid (J.Amer.Chem.Soc. 1959, 81,p2723) by reaction with diphenylphosphorylazidate and benzyl alcohol asdescribed in EP-A-0366059. Alternatively t-butyl alcohol, or4-nitrobenzyl alcohol may be used. The reaction may be carried out in anaromatic solvent e.g. toluene, benzene, xylene or pyridine. Chlorinatedsolvents such as chloroform and 1,2-dichloroethane, and polar aproticsolvents, such as glyme and dimethylformamide are also suitable. Theintermediate carbamate may also be prepared by reaction of theaforementioned acid to form the corresponding acyl azide andrearrangement to form the isocyanate. This isocyanate may then bereacted with an alcohol to form the carbamate.

Compounds of formula (III) are prepared from the intermediate carbamatesby a hydroformylation reaction (also known as the Oxo reaction) withhydrogen gas and carbon monoxide gas in the presence of a suitabletransition metal catalyst. Rhodium, ruthenium, cobalt or platinumcatalysts may be used. Chlorotris (triphenylphosphine) rhodium (I) andcarbonylhydridotris (triphenylphosphine) rhodium (I) are preferredcatalysts. Suitable pressures of hydrogen are in the range 1-100atmospheres and a pressure of approximately 20 atmospheres is preferred.The pressure of carbon monoxide is suitably in the range 1-100atmospheres and is preferably approximately 10 atmospheres. Thehydroformylation reaction may be carried out in an aromatic solvent,e.g. toluene, xylene or benzene, a non-aromatic hydrocarbon, e.g.hexane, heptane or petroleum fraction; or in a dipolar aprotic solventsuch as dimethyl formamide. Toluene is the preferred solvent. Thereaction can be carried out at a non-extreme temperature, suitably inthe range 20-100° C., and is preferably carried out at approximately 70°C.

Compounds of formula (III) are believed to be novel and accordingly, inan eighth aspect, the present invention provides novel intermediates offormula (III).

Hydrazines of formula (II) may be prepared according to the methods ofCripps et. al. J Amer. Chem. Soc. 81 (1959) p2723 and as described inEP-A0486666. Further methods for preparing these hydrazines aredescribed in the Examples hereafter.

For hydrazines of formula (II) wherein W is a group of formula (v)##STR7## the heterocyclic moiety may be constructed using themethodology described in Lin et. al., J Org. Chem., (1979), 44,p4160-4164.

A typical reaction scheme for the preparation of a compound of formula(I) is as follows: ##STR8## Wherein Z=benzyloxy carbonyl.

An alternative route for synthesising compounds of formula (I) or (Ia)is by reacting a compound of formula (II) with a compound of formula(IV) ##STR9## wherein BOC represents a tertiary butoxycarbonyl group, togive a compound of formula (I) wherein R=R¹ =H and optionally convertingthat compound into a compound of formula (I) wherein R and/or R¹ =C₁₋₄alkyl by standard alkylation techniques as hereinbefore described.

The reaction is suitably carried out in the presence of an aqueousmineral acid e.g. sulphuric acid at a non-extreme temperature, typicallyin the range 50 to 100° C. and preferably at about 80° C.

Compounds of formula (IV) may be prepared as follows. An amide offormula (X) ##STR10## can be prepared by coupling the known3-benzyloxycycloalkane-1-carboxylic acid M Maxim et al. Chem. Ber. 1957,90, 1425 with N,O-dimethylhydroxylamine hydrochloride either via theacid chloride or by the use of amide coupling agents such asdicyclohexyl carbodiimide, N,N'-carbonyl diimidazole or diphenylphosphoroazidate. The coupling may also be effected by the use of anactivated ester or by means of a mixed anhydride. The use of the acidchloride is preferred. The acid chloride may be prepared by usingthionyl chloride, phosphorus pentachloride or oxaloyl chloride, butthionyl chloride is preferred. Suitable solvents for the couplinginclude pyridine, toluene or acetronitrile or chlorinated solvents suchas dichloromethane in the presence of a base e.g. pyridine.Dichloromethane is preferred.

An amine of formula (IX) ##STR11## can be prepared from the compound offormula (X) by hydrogenolysis of the benzyloxy group using a transitionmetal catalyst and a source of hydrogen to form an intermediate alcohol.This alcohol is converted into a leaving group, for example byconversion into its tosylate or mesylate derivative, and is then reactedwith a source of azide ion to form the azide. Reduction of the azideusing a transition metal catalyst and a source of hydrogen forms the.amine of formula (IX).

Typical catalysts for the hydrogenolysis step include palladium oncarbon, palladium hydroxide on carbon, palladium black and platinumoxide. Palladium hydroxide on carbon is preferred. Suitable sources ofhydrogen include hydrogen gas at 1 to 100 atmospheres pressure, ammoniumformate and formic acid. The preferred source of hydrogen is hydrogengas at 15 atmospheres. The reaction is suitably carried out in anorganic solvent such as ethanol, methanol, ethyl acetate or acetic acidand is preferably carried out in ethanol.

Formation of the tosylate or mesylate derivative may be effected usingp-toluenesulphonyl chloride or methanesulphonyl chloride in the presenceof a base such as pyridine, triethylamine or 4-dimethylaminopyridine.Suitable solvents include pyridine, dichloromethane and toluene. The useof p-toluenesulphonyl chloride in pyridine is preferred.

Sodium azide is the preferred source of azide ion and the reaction issuitably carried out in a polar aprotic solvent e.g. dimethylformamide,dimethyl sulphoxide or N-methylpyrrolidinone at an elevated temperaturesuitably in the range of 40-170° C. Preferably, the reaction is carriedout in dimethylfornamide at approximately 80° C.

Reduction of the azide is effected by the use of a transition metalcatalyst such as palladium on carbon, palladium hydroxide on carbon,palladium black or platinum oxide in a suitable solvent e.g. an alcoholsuch as ethanol or methanol, containing a mineral acid such ashydrochloric acid or an organic acid such as acetic acid. Sources ofhydrogen include hydrogen gas at 1 to 100 atmospheres pressure, ammoniumformate and formic acid. The reduction is preferably carried out usingpalladium hydroxide on carbon in ethanol containing acetic acid under 1atmosphere of hydrogen.

The t-butyloxycarbonyl-enol ether of formula (IV) is prepared from theamine of formula (IX) by protecting the amine group, for example as itst-butyloxycarbonyl derivative, using a suitable reagent. TheN,N'-dimethylhydroxylamide moiety is then reduced to the aldehyde usinga hydride reducing agent. Wittig reaction of the aldehyde with asuitable reagent gives the compound of formula (IV).

The protection stage can be effected using reagents such as di^(t)butyldicarbonate or N-(^(t) butoxycarbonyloxy) succinimide in thepresence of a solvent. Suitable solvents are organic solvents such asdichioromethane, toluene and dioxane. The reaction is typically carriedout in the presence of an amine catalyst such as4-dimethylaminopyridine.

The reduction of the N,N'-dimethylhydroxylamide moiety is typicallycarried out using, for example, lithium aluminium hydride, which ispreferred, or diisobutylaluminium hydride in an organic solvent.Suitable solvents include toluene, tetrahydrofuran and diethylether.Tetrahydrofuran is the preferred solvent and the reduction is preferablycarried out at a temperature of approximately 0° C.

The Wittig reaction is carried out using, for example,methoxymethyltriphenylphos phonium bromide in the presence of a strongbase but methoxymethyltriphenylphosphonium bromide and strong base ispreferred. Suitable bases are n-butyl lithium, sodium hydride, sodiumamide or potassium ^(t) butoxide, which is preferred. The reaction istypically carried out in a solvent. Suitable solvents are etheralsolvents, e.g. tetrahydrofuran or glyme, or polar apotic solvents suchas dimethylformamide. Tetrahydrofuran is the preferred solvent and thereaction is suitably carried out at 0-100° C. and preferably atapproximately 80° C.

Intermediates of formula (IV) are believed to be novel and accordinglyin a further aspect, the present invention provides compounds of formula(IV).

Compounds of formula (Ia) are prepared by reacting a compound of formula(IV) wherein A is cyclobutyl with a compound of formula (II) wherein Wis Wa.

A typical reaction scheme is as follows ##STR12## Reagents: (i) SOCl₂/HN(OMe)Me, (ii) Pd/C/H₂, (iii) TsCl/pyridine, (iv) NaN₃ /DMF; (v)Pd/C/H₂ ; (vi) (BOC)₂ O; (vii) LiAlH₄ ; (viii) Ph₃ PCH₂ OMe/KO^(t) Bu;(ix) AcOH 25% eq.

Compounds wherein A is a cyclopropyl group can suitably be prepared byreacting a compound of formula (V) ##STR13## wherein BOC represents atertiary butoxy carbonyl group with a hydrazine of formula (II).

Intermediates of formula (V) are believed to be novel and accordingly,in a further aspect, the present invention provides compounds of formula(V).

A typical reaction scheme is as follows: ##STR14## Reagents: (i) N₂CHCO₂ Et/(RhOAc)₂, (ii) KOH/H₂ O, (iii) DPPA/tBuOH/PhMe, (iv) BH₃/THF/H₂ O₂ /OH--, (v) DMSO/(COCl)₂

The aldehyde of formula (V) may be prepared by oxidation of the alcohol(*). Although this alcohol has been described in U.S. Pat. No. 4988703,no indication as to stereochemistry has previously been. We have nowdiscovered methods whereby the alcohol (*) may be prepared in its puretrans form. Thus, Curtius reaction of 2-ethylenecyclopropane carboxcylicacid, according to the methods described above for the preparation ofcompounds of formula (III), gives the carbamate product. In this case,the preferred alcohol is t-butylalcohol andtrans-N-t-butoxycarbonyl-2-ethenylcyclopropylamine is isolated.

The trans-ethenyl compound so isolated is now converted into theterminal alcohol by a hydroboration reaction with oxidation of theintermediate borane by hydrogen peroxide. Typical reagents includeborane-solvent complexes, or sodium borohydride boron trifluorideetherate. The use of borane-tetrahydrofuran complex in tetrahydrofuranis preferred. Oxidation of the alcohol (*) to the aldehyde (V) may beeffected by organic or inorganic oxidants. Organic oxidants includeoxalylchloride/dimethylsulphoxide, inorganic oxidants include chromium,manganese and molybdenum complexes. Mixed organic/catalyst systems suchas N-methyl-morpholine-N-oxide/tetrapropylammonium perruthenate are alsosuitable. The preferred oxidant system isoxalylchloride/dimethylsulphoxide (known as the Swern oxidation).Suitable solvents include chlorinated and non-chlorinated organicsolvents. Dichloromethane is preferred.

An alternative scheme for the synthesis of compounds of formula (I) or(Ia) wherein one of R or R¹ is hydrogen with the other being C₁₋₄ alkylis as follows: ##STR15## Reagents: (i) (EtO)₃ CH/pTsO R, (ii) NaH/RI,(iii) 1%H₂ SO₄ /80°, (iv) Pd(OH)₂ /10%HCOOH/MeOH reflux

The invention will now be described, by way of illustration only by thefollowing examples:

The aldehyde of formula (III) may be protected as a dialkyl acetalderivative where the alkyl group may be C₁ -C₅ and may be alicyclic orcyclic. The diethylacetal is preferred. The protection may be effectedby reagents such as trialkylorthoformates or dialkoxypropanes in thepresence of an acid catalyst such as organic or mineral acids or Lewisacids. Triethylorthoformate in the presence of p-toluene sulphonic acidis preferred.

The acetal may be alkylated using a base and a suitable alkylatingagent. Suitable alkylating agents include alkyl halides,alkylsulphonates or dialkylsulphates. Methyl iodide is the preferredalkylating agent. Suitable solvents for the reaction include polaraprotic solvents, etheral solvents and alcohols. Dimethyformamide ispreferred. The alkylated acetal may now be reacted with a hydrazine offormula (II) as described above and the carbamate protecting groupremoved to give the monoalkylated product.

EXAMPLE 14-[3-(trans-3-aminocyclobutyl)-5-indolylmethyl)-(4S)-oxazolidin-2-oneand 4-[3-(cis-3-aminocyclobutyl)-5-indolylmethyl)-(4S)-oxazolidin-2-oneacetate

(a) cis and transN-Methoxy-N-methyl-3-benzyloxycyclobutane-1-carboxamide (1)

To 3-benzyloxy cyclobutane-1-carboxylic acid (8.23 g, 39.95 mmol) wasadded thionyl chloride (50 ml) and dimethyl formamide (2 drops). Thereaction was refluxed for 2 h then the thionyl chloride removed on arotary evaporator. The acid chloride was dissolved in dichloromethane(50 ml) and cooled to 0° C. The N,O-dimethyl hydroxylamine hydrochloride(4.29 g, 44 mmol) was followed by pyridine 9.71 g, 100 mmol). Thereaction was allowed to warm to r.t. and stirred overnight. Thevolatiles were removed on a rotary evaporator and the residue taken upin 10% aq. hydrochloric acid and extracted with ethylacetate. Theextracts were washed with water and dried over sodium sulphate.

Column chromatography gave the product (7.7 g, 31 mmol, 77%) as a clearoil.

HRMS for C₁₄ H₁₉ NO₃, calculated 249.13649 found 249.1354.

(b) cis and trans 3-hydroxy-N-methoxy-N-methylcyclobutane-1-carboxamide.

The benzyl ether (7.7. g, 30.9 mmol) in ethanol (250 ml) washydrogenated over 10% palladium hydroxide on carbon (1 g) at 15 atm H₂.The product was purified by column chromatography to give 4.02 g, 25.2mmol, 82%. HMS for C₇ H₁₃ NO₃, calculated 159.08954 found 159.0892.

(c) cis and trans 3-Azido-N-methoxy-N-methylcyclobutane-1-carboxamide

To the alcohol (4.02 g, 25.2 mmol) in pyridine (40 ml) at 0° C. wasadded the p-toluensulphonylchloride (5.29 g, 27.7 mmol) and the reactionstirred for 16 hrs. The volatiles were removed on a rotary evaporatorand the residue taken up in ethyl acetate (150 ml) and washed with 3%aq. hydrochloric acid in sat. brine (2×100 ml), sat. aq sodiumbicarbonate (50 ml) and dried over sodium sulphate. Chromatography gave7.47 g, 23.1 mmol, 92% of tosylated compound which was used directly forthe next stage.

To the tosylate in dimethylformamide (40 ml) was added the sodium azide(1.49 g, 23 mmol) and the reaction heated to 80° C. for 4 h. Anadditional amount of sodium azide (0.75 g, 11.5 mmol) was added andheating continued for 2 hr. The cooled reaction was poured into water(200 ml) and extracted with ethyl acetate. The extracts were dried oversodium sulphate. Column chromatography gave the product (4.1 g, 22.3mmol, 88%) as an oil. HRMS for C₇ H₁₂ O₂ ; calculated 184.09603 found184.977.

(d) cis and trans 3-Amino-N-methoxy-N-methylcyclobutane-1-carbonamide

The azide (4.1 g, 22.3mmol) in ethanol (60 ml) and acetic acid (2 ml)was hydrogenated (1 atm H₂) over 10% palladium on carbon (100 mg).Column chromatography gave the product (1.28 g, 8.1 mmol, 36%) as anoil. HRMS for C₇ H₁₂ N₂ O₂ ; calculated 158.10553 found 158.1033.

(e) cis and trans 3-^(t)butoxycarbonylamino-N-methoxy-N-methyl-1-cyclobutane carboxamide

To the amine (1.28, 8.1 mmol) and 4-dimethyl aminopyridine indichloromethane (20 ml) was added di ^(t) butylcarbonate (3.54 g, 16.2mmol) in one portion and the reaction stirred for 16 hr. Water (50 ml)was added and the reaction stirred for 30 min. The dichloromethane wasseparated and dried over sodium sulphate. Column chromatography gave theproduct as an oil (1.46 g, 5.66 mmol, 70%). Microanalysis calculated C55.81, H 8.53, N 10.85, found C55.62, H 8.87. N 10.49.

(f) cis and trans 3-t butoxycarbonylamino-cyclobutane-1-carboxaldehyde

To the methoxymethylaride (258 mg, 1 mmol) in tetrahydrofuran (5 ml) at-50° C. was added di isobutyl aluminium hydride (1.1 mol of a 1 Msolution in toluene) and the reaction allowed to warm to 0° C. for 30min, then water (20 ml) added. The mixture was extracted with ethylacetate and the extracts dried over sodium sulphate. Columnchromatography gave the pure product. Microanalysis calculated C 60.30,H 8.84, N 7.04 found C 60.30, H 8.87, N 7.02.

(g) cis and trans N-tbutoxycarbonyl-3-(2-methoxyethenyl)cyclobutane-1-amine.

To methoxymethyltriphenyl phosphonium bromide/sodium amide (0.23 mmol)was added tetrahydrofuran (5 ml) and the reaction stirred for 30 min.The aldehyde (30 mg, 0.151 mmol) in tetrahydrofuran (0.5 ml) was addeddropwise and the reaction heated to 80° C. for 4hr. The cooled reactionmixture was poured into water (20 ml) and extracted with ethyl acetate(2×20 ml). The extracts were dried over sodium sulphate. Columnchromatography gave the product. (14.3 mg, 0.063 mmol, 42%) as an oil.

(h)4-[3-(trans-3-aminocyclobutyl)-5-indolylmethyl)-(4S)-oxazolidin-2-oneacetate, and4-[3-(cis-3-aminocyclobutyl)-5-indolymethyl]-(4S)-oxazolidin-2-oneacetate.

To the appropriate hydrazine (310 mg, 1.5 mmol) in 1% aq sulphuric acid(10 ml) was added the methylenol ether (˜1 mmol) and the reaction heatedto 80° C. for 6 hrs. The reaction was cooled and washed with ethylacetate. The acidic layer was saturated with sodium chloride andextracted with tetrahydrofuran. the extracts were dried over sodiumsulphate. Column and HPLC chromatography gave the trans product (gum)HRMS calculated for C₁₆ H₁₉ N₃ O₂ 285.14773 found 285.1477 and the cisproduct mpt 180-181° C. HRMS calculated 285.14773 found 285.1458.

EXAMPLE 2Trans-4-[3-(3-(dimethylaminocyclobutyl)-5-indolylmethyl]-(S)-1,3oxazolidin-2-one

(a) Trans-N-benzyloxy carbonyl)-cyclobutanamine-3-acetaldehyde

Trans-N-(benzyloxycarbonyl)-3-methylenecyclobutanamine (18 g, 83mmol)(prepared as described in EP-A-0366059) andtris(triphenylphosphine)rhodium chloride (400 mg 0.43 mmol) were heatedto 70° C. in toluene (250 ml) under 100 atmospheres of CO:H₂ (1:1mixture for 18 hrs. The solvent was evaporated under reduced pressureand the residue chromatographed on silica eluting with 25% ethylacetatein cyclohexane. First product eluted (r.f.˜0.25) mixture of cis andtrans branched chain aldehydes. Second product eluted (r.f.˜0.1) mixtureof cis and trans straight chain aldehydes. the trans isomer wascrystallized from ether as white needles (mpt=66-67° C.). Microanalysisfor C₁₄ H₁₇ NO₃ Calculated C 68.02, H 6.88, N 5.67 Found C 67.92, H6.90, N 5.63.

(b)4-[3-(trans-3-aminocyclobutyl)-1H-indol-5-ylmethyl-(4S)-oxazolidin-2-one

The appropriate hydrazine (6.3 g, 30 mmol) andtrans-N-(benzyloxycarbonyl)cyclobutanamine-3-acetaldehyde (6.3 g, 25.5mmol) were heated to 80° C. for 7 hours in 1% sulphuric acid (aq) (100ml) and ethanol (150 ml). The reaction mixture was evaporated in vacuoand brine added. Extraction with ethyl acetate gave the crude product(10.5 g, 83%) MS (FAB) 420 (M+1)⁺.

The product from the above was refluxed in 10% formic acid-methanol withpalladium hydroxide on carbon (1 g) for 7 hours. The solvent was removedin vacuo and brine added. The solution was then washed with ethylacetate and then made basic (pH 10-12) with dil. ammonium hydroxidesolution. Extraction with THF gave the crude product which was purifiedby flash chromatography (2:14:84 NH₃, ETOH₃) (2 g, 28%) MS (FAB) 286(M+1)⁺.

(c)Trans4-[3-(3-dimethylaminocyclobutyl)-5-indolylmethyl]-(S)-1,3-oxazolidin-2-one

Formaldehyde (0.18 ml, 2,22 mmol) in methanol (5 ml) was added to theproduct of step (b) (250 mg, 0.88 mmol), acetic acid (0.26 ml, 4.55mmol) and sodium cyanoborohydride (70 mg, 1.17 mmol) in methanol (15 ml)and stirred at room temperature under a nitrogen atmosphere overnight.

Water was added and the mixture washed with ethylacetate. The aqueousphase was then adjusted to pH 10 with potassium carbonate and saturatedwith sodium chloride.

Extraction with ethylacetate gave a sticky gum which was chromatographedon silica eluting with 1% 0.88 NH₃ solution in methanol (r.f.˜0.4) togive an off white powder. Elemental analysis for C₁₈ H₂₃ N₃ O₂ 0.35CHCl₃ Calculated C 62.05, H 6.63, N 11.83 Found C 62.21, H 6.76, N 11.55mpt=Becomes gummy at 77-78° C.

This solvated compound can be dried in vacuo at 80° C. to provide theanhydrous compound of Example 4.

The following compounds were made by selecting appropriate startingmaterials and following the method described in Example 2.

    ______________________________________                                        Example                                                                         No. W n A R R.sup.1 isomer                                                  ______________________________________                                          3.  Melt-  ing  point  197-  199° C.                                                                              2 cyclo-  butyl Me Me trans                                                   - 4.  M. pt.  159-  160.degre                                               e. C.                                                                           1 cyclo-  butyl Me Me (S)                                                   trans                                 - 5.  M. pt.  67-  69° C.                                                                                        2 cyclo-  butyl Me Me trans                                                   - 6.  M. pt.  85-  87°                                                C.                                                                             2 cyclo-  butyl H H trans                                                     - 7.  M. pt.  52-  53°                                                C.                                                                             2 cyclo-  butyl Me Me trans                                                   - 8.  M. pt.  66-  68°                                                C.                                                                             2 cyclo-  butyl Me Me trans                                                   - 9.  M. pt.  106-  109.degre                                               e. C.  dec.                                                                     1 cyclo-  butyl Me Me trans                                                   - 10.  M. pt  220-  222.degre                                               e. C. SO.sub.2 NHMe 1 cyclo-                                                  butyl Me Me trans                     - □                                                               11.  M. pt.  163-  165° C.                                                                                        1 cyclo-  butyl Me Me (R)                                                   trans                                 - 12.  M. pt.  70-  72° C.                                                                                       1 cyclo-  butyl Me Me trans                                                   - 13.  M. pt.  foam                                                           1 cyclo-  butyl Me Me (R)-                                                  trans                                 - 14. CONH.sub.2 0 cyclo- Me Me trans                                        M. pt.   butyl                                                                93-  95° C.                                                             - 15.  Hydro-  scopic                                                                                                   1 cyclo-  butyl Me Me                                                       (S)-cis                               - 16. OPh 0 cyclo- H H trans                                                 M. pt.   butyl                                                                164-                                                                          166° C.                                                                17. OPh 0 cyclo- Me Me trans                                                  M. pt.   butyl                                                                189-                                                                          190° C.                                                                 - 18.  M. pt.  foam                                                                                                     0 cyclo-  butyl Me Me trans                                                   - 19.  M. pt.  foam                                                           1 methyl  cyclo-  butyl Me                                                  Me (S)  trans                      ______________________________________                                    

EXAMPLE 20 Alternative synthesis for 4-[3-(Trans-3-aminocyclobutyl)-5-indolylmethyl]-(4S)-oxazolidin-2-one: Compound of Example 1

The trans-N-(benzyloxycarbonyl)-cyclobutanamine-3-acetaldehyde (1 g, 4mmol) and hydrazine (1.2 g, 5.8 mmol) were heated to 80° C. in 1%aqueous sulphuric acid (50 ml) for 6 hours. After cooling the solid wasfiltered off and dried under vacuum. Used crude for next stage.mpt=95-100° C. The Cbz protected indole (500 mg, 1.2 mmol) and palladiumhydroxide on carbon (50 mg, 0.36 mmol) were refluxed in 10% formic acidin methanol (25 ml) for 3 hours. The catalyst was filtered off and thesolvent evaporated under reduced pressure. Brine was added to theresidue and the pH adjusted to 11 with 0.88 ammonium solution. The milkysolution was extracted with tetrahydrofuran, dried over MgSO₄ andevaporated under vacuum to give the free base as a foam. HRMS Calculated285.1477. Found 285.1485.

EXAMPLE 21 (+)-5-[3-trans-3-dimethylaminocyclobutyl)-1H-indol-5-lmethyl]oxazolidin-2-one

(a) 5-benzyl-2-oxazolidin-2-one

2,3-Epoxypropylbenzene (60 g, 448 mmol) and potassium cyanate (70 g, 364mmol) were refluxed in DMNF (600 ml) and water (300 ml) for 4 hours. Thesolvent was evaporated in vacuo and water added. The aqueous was thenextracted with ethyl acetate, dried (Mg SO₄) and evaporated.Recrystallization from ethyl acetate gave the product (28.2 g, 36%) Mpt106-107° C. MS (EI) 177 (M+), 133, 86.

(b) 5-(4-nitrobenzyl)-2-oxazolidinone

4-benzyl-2-oxazolidinone (5 g, 28 mmol), potassium nitrate (2.9 g, 29mmol) and p-iodotoluene (0.5 g, 2 mmol) were stirred in trifluoraceticacid (50 ml) overnight. The mixture was then poured onto ice andextracted with ethyl acetate. This was washed with sodium bicarbonatesolution, dried (Mg SO₄) and evaporated. Flash chromatography (70:30ethyl acetate/hexane) gave the product (2.2 g, 35%) Mpt 150-151° C., MS(ES) 223 (M+1)+

(c) 5-(4-aminobenzyl)-2-oxazolidinone

4-(4-nitrobenzyl)-2-oxazolidone (9.9 g, 45 mmol) and 10% palladium oncarbon (900 mg) were stirred under a hydrogen atmosphere in methanol(200 ml) and 2.5N aq. HCl (50 ml) at room temperature for 4 hours. Thereaction mixture was filtered and evaporated. Water was added and thesolution washed with ethyl acetate. The aqueous phase was then basifiedwith dil NaOH solution and extracted with THF to give the crude product(6.2 g, 72%) Mpt 135-138° C. MS(EI) 192 (M+), 106,

The 5-(4-ainobenzyl)-2-oxazolidinone (1.7 g, 8.9 mmol) was disolved inc.HCl (2 ml) and water (7.5 ml) and then cooled to below 50° C. Asolution of sodium nitrite (0.61 g 7 mmol) in water (7.7 ml) was thenadded dropwise. The solution was then stirred at ˜5° C. for 20 minutes.This was then added slowly to a cooled solution (below 5° C.) of sodiumsulphite (3.4 g, 27 mmol) in water (15 ml). The solution was stirred for20 minutes before allowing it to warm to room temperature and thenheating slowly to 60° C. c.HCl (3ml) was then added and heating at 60°C. continued overnight. The solution was then diluted with water (15 ml)and ethanol (30 ml). Trans-N-(benyloxycarbonyl)cyclobutanamine-3-acetaldehyde (1.5 g, 6 mmol) was then added and themixture heated to 80° C. for 7 hours. Partial evaporation followed byextraction with THF gave the crude product which was purified by flashchromatography (5:95 methanol/chloroform) (1.7 g, 46%) MS (FAB) 420(M+1)+

The product of this step was then treated by methods outlined in example2 to provide(±-5-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]oxazo-lidin-2-one.

EXAMPLE 22 4-[3 -(trans-3-methylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one

(a) Trans-N-(benzyloxycarbonyl) cyclobutanamine-3-acetaldehyde diethylacetal

Trans-N-(benzyloxycarbonyl)cyclobutanamine-3-acetaldehyde (1 g, 4 mmol),triethylorthoformate (1.35 ml, 8 mmol) and p-toluene sulphonic acid (100mg) were refluxed in ethanol for 3 hours. The reaction mixture wasevaporated in vacuo and purified by flash chromatography (10:90 Ethylacetate/cyclohexanone) to give a colourless oil (1.2 g, 94%).

(b) Trans-N-benzyloxycarbonyl-N-methyl cyclobutanamine-3-acetaldehydediethyl acetal

Trans-N-(benzyloxycarbonyl) cyclobutanamine-3-acetaldehyde diethylacetal (1.2 g, 3.7 mmol) in dry DMF,(10 ml) was added dropwise to a coldsuspension of sodium hydride (60% in oil) (165 mg, 4.1 mmol) in dry DMF(1 ml). After the addition was complete the mixture was allowed tostirred at 10° C. for 1/2 hour. Methyl iodide (0.23 ml, 3.7 mmol) in dryDMF (5 ml) was then added dropwise. The mixture was then allowed to warmto room temperature and stir for 2 hours. The reaction was then pouredonto ice and extracted with ether. Flash chromatography (10:90ethylacetate/cyclohexane) gave the product as a colourless oil (1 g,83%).

The product of this step was then treated by methods outlined in example2 to provide4-[3-(trans-3-methylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)oxazolidin-2-one.

EXAMPLE 235-N-benzylcarboxamido-3-trans-3-dimethylaminocyclobutyl)-1H-indole

(a) 3-(trans-3-dimethylaminocyclobutyl)1H-indole-5-carboxylic acid

5-carboxamido-3-(trans-3-dimethylaminocyclobutyl)-1H-indole (0.4 g, 1.6mmol), prepared using the methods described in example 2, was refluxedin 10M NaOH solution (15 ml) and methanol (10 ml) for 7 hours. Theresulting solution was cooled in ice and neutralized with dil HCl. Thiswas then evaporated to dryness in vacuo and methanol added. The sodiumchloride was filtered off and the solution evaporated to give the crudeproduct.

(b) 5-N-benzylcarboxamido-3-trans-3-dimethylaminecyclobutyl)-1H-indole

The crude 3-(trans-3-dimethylaminocyclobutyl)-1H-indole-5-carboxylicacid (0.4 g, 1.6 mmol), 0-(1H-benzotriazol-1-yl)-N,N,N¹ N¹-tetramethyluronium tetrafluoroborate (0.57 g, 1.8 mmol), benzylamine(0.18 ml, 1.6 mmol) and triethylamine (0.25, 1.8 mmol) were stirred atroom temperature in dry DMF (15 ml) for 5 hours. The reaction wasquenched with water and extracted with ethyl acetate. This was dried(MgSO₄) and evaporated to give the crude product which was purified byflash chromatography (1:10:89 0.88 NH₃, MeOH, CHCl₃) (175 mg, 32%)MS(EI) 347 (M+).

EXAMPLE 24 2-{2-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-yl]ethyl} phthalamide

The Cbz protected intermediate prepared by methods described in example2, (0.5 g, 1.6 mmol), boron trifluoride etherate (2 ml, 16 mmol) andethylmercaptan (3.4 ml, 46 mmol) were refluxed for 48 hours. The mixturewas then evaporated in vacuo and brine added. The pH was then adjustedto pH10-12 with dil NaOH solution. Extraction with THF gave the crudeproduct which was chromatographed on silica eluting with 1:99 0.88 NH₃/MeOH. (190 mg, 33%) MS (FAB) 360 (M+1)+.

The product of this step was then treated by methods outlined in example2 to provide 2-{2-[3-trans-3-dimethylaminocyclobutyl)-1H-indol-5-yl]ethyl} phthal-amide.

EXAMPLE 25 3-[trans-3 -dimethylaminocyclobutyl]-1H-indol-5-yl acetamide

(a) 4-hydrazinophenylacetic acid hydrochloride

To a solution containing conc. HCl (76 ml) and 4-amino phenylacetic acid(10 g: 66 mmol) at 40° C. was added a solution of sodium nitrite (4.56g; 55 mmol) in water (10 ml) dropwise, while maintaining the temperatureat 0 to 4° C. The mixture was stirred for 30 minutes and added to a cold(0° C.) solution of SnCl₂ (74.5 g 331 mmol) in conc. HCl (50 ml). Themixture was left to warm to room temperature overnight. The precipitateformed was filtered and washed with water (50 ml), 50% aq.HCl (50 ml),water (50 ml) and ether (2×50 ml). The solid was dried in vacuo to givethe product 13 g. M.pt. 220-223° C. dec.

MS. 166(M+) 151, 135, 121

NMR [360 Mz, ¹ H] ppm 3.5 (s, 2H) 6.9 (d, 2H) 7.1 (d, 2H), 10.7 (bs).

(b)3-[trans-N-(benzyloxycarbonyl)-3-aminocyclobutyl]-1H-indol-5-ylacetic acid

To 4-hydrazinophenylacetic HCl. in 1% aq. sulphuric acid (75 ml) wasadded trans-N-(benzyloxycarbonyl)cyclobutanamine-3-acetaldehyde (5 g, 20mmol). The mixture was heated to 90° C. for 7 hours. The semi-solidformed was filtered and washed with 1% H₂ SO₄ and water. The solid wasthen taken up into ethyl acetate and washed with water. The organicphase was dried (MgSO₄). The product was obtained as a sticky solid.Yield: 6.5 g (74%).

(c)3-[trans-N-(benzyloxycarbonyl)-3-aminocyclobutyl]-1H-indole-5-ylacetamid

To a solution of3-[trans-N-(benzyloxycarbonyl)cyclobutanamine]-1H-indol-5-yl acetic acid(0.5 g, 1.38 mmol) in DMF (5 ml) was added0-(3,4-dihydro-4-oxo-1,2,3-benzotriazine-3-yl) N,N,N¹,N¹-tetramethyluronium tetrafluoroborate [TBTU] (0.44 g; 1.38 mmol) and Et³N (0.21 ml: 1.52 mmol). Anhydrous ammonia was then bubbled through thesolution for 1 hour at room temperature with cooling in ice asnecessary. The mixture was stirred overnight at room temperature. Thesolvent was evaporated under vacuum. The residue was chromatographed onsilica using MeOH (10%)/chloroform (89%)/880 NH₃ (11%). Yield 0.28 g(56%) MS 269, 253, 182 NMR [360MH₃, H¹ ] 2.49 (t, 4H) 3.3 (m, 2H), 3.55(m 1H) 4.11 (m 1H); 5.0 (m 3H), 6.78 (bs 1H), 6.98 (dd 1.6HZ, 8.5 HZ;1H) 7.3 (m.9) 7.7 (d 6.8 HZ, 1H).

The product of this step was then treated by methods outlined in example2 to provide 3-[trans-3-dimethylaminocyclobutyl]-1H-indol-5-ylacetamide.

EXAMPLE 26 N-benzyl-3-[trans-3-dimethylaminocyclobutyl]-1H-indol-5-ylacetamide

(a)N-benzyl-3-[trans-3-(benzyloxycarbonylamino)cyclobutyl]-1H-indol-5-ylacetamide

To a solution of3-[trans-N-(benzyloxycarbonyl)-3-aminocyclobutyl]indol-5-yl acetic acid(1 g, 2.76 mmol) in DMF (5 ml) was added TBTU (0.97 g 3.04 mmol), Et₃ N(0.42 ml 3.04 mmol) and benzylamine (0.33 ml 3.04 mmol). The mixture wasstirred overnight at room temperature. The solvent was evaporated undervacuum and the residue chromatographed on Silica 5% MeOH/94% CHCl₃ /1%880 NH3 to give a pale yellow oil. yield: 0.81 g (80%) MS 468 (M+1),392, 333.

The product of this step was then treated by methods outlined in example2 to provide N-benzyl-3-[trans-3-dimethylaminocyclobutyl]-1H-indol5-ylacetamide

EXAMPLE 273-methyl-5-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]1,2,4-oxadiazole

(a)N-[(dimethylamino)ethylidene]-3-[trans-3-(benzyloxycarbonylamino)cyclobutyl]-1H-indol-5-ylacetamide

To a solution containing3-[trans-N-benzyloxycarbonyl-3-aminocyclobutyl]indol-5-yl acetamide(4.68 g 13 mmol) in toluene (10 ml) was added N,N-dimethyl acetamidedimethyl acetal (40 ml). The mixture was then heated at 120° C. for 2hours under Dean & Stark conditions. The solution becomes very dark. Thesolvent is evaporated under vacuum to giveN-[(dimethylamino)ethanylidene]-3-[trans-3-(benzyloxycarbonylamino)cyclobutyl]-1H-indol-5-ylacetamide.

Yield 5.7 g crude.

(b) 5-{3-[N-(benzyloxycarbonyl)-trans-3-dimethylaminocyclobutyl]-1H-indol-5-yl}-3-methyl-1,2,4-oxadiazole

To a mixture containing hydroxylamine HCl, (10 mg 1.6 mmol) 5N NaOH (0.2ml), p-dioxane (3 ml) and 70% acetic acid (10 ml) was added the amidine(500 mg 1.6 mmol) and the mixture heated to 120° C. for 11/2 hours. Thesolvent was evaporated under vacuum and the residue was chromatographedusing silica and 40% EtOAc/60% cyclohexane to give the product.

Yield: 150 mg (31%) as a foam

MS 417 (M+1) 296

The product of this step was then treated by methods outlined in example2 to provide3-methyl-5-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-1,2,4-oxadiazole.

EXAMPLE 283-methyl-5-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]1,2,4-triazole

(a) To a solution of the amidine, prepared as in example 35 (a) above,(3 g, 6.99mmol) in 70% aqueous acetic acid (100 ml), was added hydrazinehydrate 10.9 ml, 8.39 mmol). The mixture was stirred at 90° C. for 5hours. The mixture was concentrated under reduced pressure and dilutedwith water (100 ml). The aqueous phase was extracted with ethyl acetate(2×50 nm). The organic phase was dried (MgSO₄) and evaporated. Theresidue was chromatographed using 10% MeOH/189% CHCl₃ /%NH₃ to give anoil.

Yield : 200 mg

MS 416 (M+1), 415 (m⁻) 326

The product of this step was then treated by methods outlined in example2 to provide3-methyl-5-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-1,2,4triazole.

EXAMPLE 29(S)-2-(5-(2-Oxo4-oxazolidinylmethyl)-1H-indol-3-yl)cyclopropylamine

a) Ethyl 2-ethenylcyclopropane Carboxylate

Butadiene (200 ml, Aldrich) condensed at -700 was transferred to a glasslined autoclave vessel and ethyl diazoacetate (20 g, 0.175 mol, Aldrich)and rhodium acetate dimer (0.3 g, Aldrich) added. The suspension wasstirred in a sealed autoclave for 24 hours at ambient temperature. Thecontents were diluted with 2% diethyl ether in pentane and passedthrough a silica pad (50 g). The pad was washed with a little ethanoland further ether-pentane. The eluant containing ethanol was treatedseparately. The organic phases were concentrated at reduced pressure(<5°) and subjected to short path bulb to bulb disillation (90-105° at12 mm) to give the product as a colourless liquid (14.6 g).

b) 2-Ethylenecyclopropanecarboxylic Acid

The above ester (11.79 g, 84.21 mmol) was dissolved in tetrahydrofuran(THF) (16 ml) and treated with potassium hydroxide (7.32 g) in water (75ml) and heated under gentle reflux for 5 hours. The reaction mixture wasconcentrated and the residue dissolved in water. This was acidified withconc. hydrochloric acid to pH 4 and the emulsion was extracted withdiethyl ether. The organic phase was dried, concentrated and theresidual oil distilled (100-120° at 3 mm) to give the product as acolourless liquid (8.7 g).

c) trans-N-t-Butoxycarbonyl-2-ethenylcyclopropylamine

The above acid (8.66 g, 77.43 mmol) was dissolved in anhydrous toluene(40 ml), cooled to 0°, treated with dry triethylamine (11.9 ml) andthen, dropwise, with diphenylphosphoryl azide (23.4 g, Aldrich) intoluene (25 ml). The solution was warmed to 80° and kept at 80-85° for45 mins. Anhydrous t-butanol (36 ml) and toluene (10 ml) were addedquickly and the solution heated at 102° for 6 hours. The reactionmixture was allowed to cool and diluted with diethyl ether, washed with1N orthophosphoric acid (100 ml), saturated aq.sodium bicarbonate andbrine, dried and concentrated. The residual oil was purified bychromatography (silica: 350 g; hexane: ethyl acetate 95:5) to give theproduct as a colourless oil (3.91 g).

d) trans-N-t-Butoxycarbonyl-2-(2-hydroxyethyl)cyclopropylamine

The above alkene (3.91 g, 21.37 mmol) in anhydrous THF (20 ml) wascooled to 0° and treated with borane : TBF complex (42.7 ml, 1M in THF,Aldric). Stirred at 0° for 2.5 hours then allowed to reach ambienttemperature, recooled to -5° and treated sequentially with 6N aq.sodiumhydroxide (24.8 ml) and 30% aq. hydrogen peroxide (7.53 ml). The mixturewas stirred at room temperature for 10 mins then treated with excesssolid potassium carbonate and extracted with ethyl acetate (3×100 ml).The organic phase was washed once with aq. orthophosphoric acid,aq.sodium bicarbonate, brine and dried. The solvent was removed andresidual oil subjected to chromatography (silica : 300 g; 1% to 4%methanol in dichloromethane) to give the product as an oil whichcrystallised upon standing at 3° (4.1 g).

e) trans-N-t-Butoxycarbonyl-2-(2-oxo-ethyl)cyclopropylamine

Oxalyl chloride (175 ml) in dry dichloromethane (DCM (8 ml) was cooledto -65° and treated with dimethyl sulphoxide (316 mg) in DCM (1 ml) andafter 10 mins. the above alcohol (394 mg, 1.96 mmol) in DCM (2 ml) wasadded. After 1 hour at -65° triethylamine (1.1 ml) was added andreaction allowed to reach 0° and diluted with diethyl ether (25 ml). Theorganic phase was washed with water, 1N orthophosphoric acid,satd.aq.sodium bicarbonate and brine and dried. The solvents wereremoved to give the product as a pale yellow oil (349 mg).

f) (S)-2-(5-(2-Oxo-4-oxazolidinylmethyl)-1H-indol-3-yl)cyclopropylamine

The above aldehyde (349 mg, 1.75 mmol) was treated with 3:1 water:acetic acid (25 ml) and(S)-4-(2-oxo-4-oxazolidinylmethyl)phenylhydrazine (440 mg, 2.12 mmol).The mixture was heated under nitrogen at 80-85° for 5 hours. Thereaction mixture was concentrated, DCM, ethanol, 880 ammonia (85:15:1)added and reconcentrated. The residue was subjected to chromatography(silica: 50 g; DCM, ethanol, ammonia (85:15:1) and the component (R_(f).0.10; silica-DCM methanol, ammonia (90:10:1) isolated. The latter wassubjected to purification (x2) by preparative HPLC (Zorbax C₈, MeCN-0.1Maq.NH₄ OAc) to give the title compound as a yellow foam in the form ofan acetate salt.

7.45(1H,s,2-H; 7.70 (1H,s,NH); 10.57 (1s,indole NH).

Accurate mass; 271.13208 (C₁₅ H₁₇ N₃ O₂)

Pharmaceutical Formation Examples

In the following Examples, the "active ingredient" may be any compoundof formula (I) or (Ia) and/or a physiologically acceptable salt,solvate, or physiologically functional derivative thereof

(1) Tablet formulations

(i) Oral

    ______________________________________                                                         Mg/tablet                                                                     A    B                                                       ______________________________________                                        Active ingredient  2.5    2.5                                                   Avicel 13 --                                                                  Lactose 100.5 69.5                                                            Starch (maize) -- 9                                                           Sodium starch 5 --                                                            glycollate                                                                    Povidone 3 3                                                                  Magnesium stearate 1 1                                                         125 85                                                                     ______________________________________                                    

Formulations A to C may be prepared by wet granulation of the first sixingredients with the povidone, followed by addition of the magnesiumstearate and compression.

(ii) Buccal

    ______________________________________                                                       Mg/tablet                                                      ______________________________________                                        Active ingredient                                                                              2.5                                                            Hydroxypropylmethyl                                                           cellulose (HPMC) 35                                                           Polycarbophil 51.5                                                            Magnesium stearate 1                                                           90                                                                         ______________________________________                                    

The formulation may be prepared by direct compression of the admixedingredients.

(2) Capsule formulations

(i) Powder

    ______________________________________                                                         Mg/Capsule                                                                    D    E                                                       ______________________________________                                        Active ingredient  2.5    2.5                                                   Lactose 175.5 --                                                              Starch (1500 NF) 45 139.5                                                     Sodium starch -- 6                                                            glycollate                                                                    Magnesium stearate 2 2                                                         225 150                                                                    ______________________________________                                    

Formulations D and E may be prepared by admixing the ingredients andfilling two-part hard gelatin capsules with the resulting mixture.

(ii) Liquid fill

    ______________________________________                                                         Mg/Capsule                                                                    F    G                                                       ______________________________________                                        Active ingredient  2.5    2.5                                                   Macrogol 4000 BP 222.5 --                                                     Lecithin -- 110                                                               Arachis oil --  112.5                                                          225 225                                                                    ______________________________________                                    

Formulation F may be prepared by melting the Macrogol 4000 BP,dispersing the active ingredient in the melt and filling two-part hardgelatin capsules therewith. Formulation G may be prepared by dispersingthe active ingredient in the lecithin and arachis oil and filling soft,elastic gelatin capsules with the dispersion.

(iii) Controlled Release

    ______________________________________                                                      Mg/tablet                                                       ______________________________________                                        Active ingredient                                                                             2.5                                                             Avicel 145.5                                                                  Lactose 62                                                                    Triethylcitrate 3                                                             Ethyl cellulose 12                                                             225                                                                        ______________________________________                                    

The formulation may be prepared by mixing and extruding the first fouringredients and spheronising and drying the extrudate. The dried pelletsare coated with ethyl cellulose as a release controlling membrane andfilled into two-part, hard gelatin capsules.

(3) Intravenous Injection Formulation

    ______________________________________                                                      % by weight                                                     ______________________________________                                        Active ingredient                                                                             2%                                                              Hydrochloric acid ) q.s. to pH 7                                              Citrate buffer)                                                               Water for Injections to 100%                                                ______________________________________                                    

The active ingredient is taken up in the citrate buffer and sufficienthydrochloric acid added to affect solution and adjust the pH to 7. Theresulting solution is made up to volume and filtered through a microporefilter into sterile glass vials which are sealed and oversealed.

Biological Assays

A: Rabbit Saphenous Vein Assay

Compounds of formula (I) prepared in Synthetic Examples 1 to 17 wereeach tested for their activity as agonists for their activity asagonists for the "5-HT₁ -like" receptor mediating smooth musclecontraction by the following method.

Right and left lateral saphenous veins were obtained from male NewZealand White Rabbits (2.4-2.7 kg) which had been killed by intravenousinjection of pentobarbitone sodium (60 mg/kg). Ring segments (3-5 mmwide) prepared from each vessel were suspended between two wire hooksand immersed in 20 ml organ baths containing Krebs' solution (pH 7.4) ofthe following composition (mM): NaCl 118.41, NaHCO₃ 25.00, KCl 4.75, KH₂PO₄ 1.19, MgSO₄ 1.19, glucose 11.10 and CaCl₂ 2.50. Cocaine (30pL) waspresent in the Krebs' solution throughout the experiment to prevent theuptake of amines by sympathetic neurones. The Krebs' solution wasmaintained at 37° C. and continually gassed with 95% oxygen/5% carbondioxide. Increases in tissue isometric force were measure using GrassFT03C force displacement transducers and recorded on a Gould BD-212 penrecorder.

A force of 1.0 g was applied to each preparation and re-establishedtwice during a subsequent period of 30 minutes. During this period,tissues were exposed to pargyline (500 μM) to irreversibly inhibitmonoamine oxidase and to phenoxybenzamine (0. μM) to inactivate α₁-adrenoceptors. At the end of the 30 minutes, the inhibitors wereremoved by several changes of the organ bath Krebs' solution.

Agonist activity was assessed by simulative additions of the testcompound, its concentration being increased in 0.5 log₁₀ unit incrementsuntil further additions caused no further change in tissue force. Ineach experiment, the activity of the test compound was compared to theactivity of 5-HT. Activity was expressed in terms of the p(A₅₀ ](-log₁₀[M] where M is the molar concentration of agonist required to producehalf the maximum effect). Where the compounds were found to beantagonists, the results are expressed as pKb. The results obtained forthe compounds of Synthetic Examples 1 to 19 and 21 to 28 are shown inTable 1.

                  TABLE 1                                                         ______________________________________                                        Example        pA.sub.50 pKbalpha.)                                           ______________________________________                                         1 (trans)     6.42 (0.78)                                                       1 (cis)  5.8 (0.76)                                                           3  5.72                                                                       4 5.72 (0.09)                                                                 5  6.05                                                                       6  5.57                                                                       7  6.77                                                                       8  7.18                                                                       9  5.03                                                                      10  5.25                                                                      11  4.95                                                                      12  6.23                                                                      13 4.85 (0.38)                                                                14 6.25 (0.52)                                                                15 5.15 (0.29)                                                                16  <6.5                                                                      17  6.62                                                                      18  6.02                                                                      19  5.73                                                                      21 5.44 (0.16)                                                                22 6.15 (0.72)                                                                23  5.90                                                                      24 5.21 (0.48)                                                                25  4.78                                                                      26  5.41                                                                      27  3.12                                                                      28  5.18                                                                    ______________________________________                                    

B: Calf Caudate Assay

Compounds of formula (I) prepared in Synthetic Examples 1 to werefurther tested for their activity as agonist for the "5-HT₁ -like"receptor mediating smooth muscle contraction by the following method

Membranes were prepared from homogenates of calf caudate nucleus.Competition binding studies were performed with 3.5 nM [³ H]-5HT(approx. 25Ciml-¹) in the presence of 15 μM mesulergine and 15 μM8-OH-DPAT, using 5 mg wet weight ml-¹ of membranes in a total volume of1 ml per tube. Binding data was fitted to a four parameter logisticfunction to obtain estimates of pIC₅₀. These were converted to pK:values using the Cheng-Prussof equation.

The results obtained for the compounds of Synthetic Examples 1 and 2 areshown in Table 2.

                  TABLE 2                                                         ______________________________________                                                      Activity                                                          Example P[A.sub.50 ]                                                        ______________________________________                                               1      7.8                                                               2 7.05                                                                      ______________________________________                                    

We claim:
 1. A compound of formula (I) ##STR29## wherein R and R¹ areeach independently hydrogen or C₁₋₄ alkyl or R and R¹ are linked to forman azetidine ring;A is C₃₋₆ cycloalkyl or C₁₋₃ alkyl-C₃₋₆ cycloalkyl; nis an integer of from 0 to 3; W is ##STR30## wherein Y is oxygen orsulfur; or a salt, solvate or physiologically functional derivativethereof.
 2. A compound of claim 1 wherein:R and R¹ are eachindependently hydrogen or C₁₋₄ alkyl; A is C₃₋₆ cycloalkyl; or a salt,solvate or physiologically functional derivative thereof.
 3. A compoundof formula (Ia): ##STR31## wherein Ra and Ra¹ are each independentlyhydrogen or C₁₋₄ alkyl;n is an integer of from 0 to 3; Wa is ##STR32##wherein Y is oxygen or sulfur; or a salt, solvate or physiologicallyfunctional derivative thereof.
 4. A compound whichis2-{2-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-yl]ethyl}phthalimideor a physiologically acceptable salt, solvate or physiologicallyfunctional derivative thereof.
 5. A pharmaceutical compositioncomprising as an active ingredient at least one compound of claim 1and/or a pharmacologically acceptable salt or solvate thereof togetherwith at least one pharmaceutically acceptable carrier or excipient.
 6. Amethod for the prophylaxis or treatment of a clinical condition in amammal for which a 5-HT₁ -like receptor agonist is indicated whichcomprises administering a compound of claim 1 in an effective amount. 7.A method according to claim 6 wherein the clinical condition ismigraine.
 8. A process for the preparation of a compound of claim 1 orclaim 3 which process comprises:a) reacting a compound of formula (II)##STR33## with a compound of formula (III) ##STR34## wherein Z is abenzyloxycarbonyl group and then removing the benzyloxycarbonyl group togive a compound wherein R_(a) =R¹ =H and optionally converting thatcompound into a compound of formula (I) wherein R and/or R¹ is C₁₋₄alkyl by N-alkylation;or b) reacting a compound of formula (II) with acompound of formula (IV) ##STR35## wherein BOC is tertiary butoxycarbonyl, to give a compound of formula (I) wherein R=R¹ =H andoptionally converting that compound into a compound of formula (I)wherein R and/or R¹ is C₁₋₄ alkyl by N-alkylation;or c) when it isdesired to prepare a compound wherein A is a cyclopropyl group, reactinga compound of formula (II) with a compound of formula (V) ##STR36##wherein BOC is tertiary butoxycarbonyl to give a compound of formula (I)wherein R=R¹ =H and optionally converting that compound into a compoundof formula (I) wherein R and/or R¹ is C₁₋₄ alkyl by N-alkylation.